This translocation is thought to bring Sos into close proximity with Ras, leading to the activation of Ras. Once Ras is activated, it proceeds to stimulate a cascade of protein kinases that are important in a myriad of growth factor responses.
Abstract Ras, a small GTP-binding protein, is an important component of the signal transduction pathway used by growth factors to initiate cell growth and differentiation. Although the affinity of kinases for ATP are usually in the micromolar range, 65 picomolar nucleotide affinities of Ras combined with millimolar intracellular nucleotide pools complicate the use of GTP-competitive inhibitors.
Libraries of GTP analogs with alternations at the ribose or nucleotide moiety 66 and of pyrazolo[3,4-b]quinoline ribosides 67 yielded molecules with moderately increased affinity compared with GDP and relatively weak inhibitory potency.
Early examples of GEF inhibitors were identified from a compound library whose members were originally designed to compete with GDP for nucleotide binding. SCH and its derivatives target a hydrophobic pocket close to the nucleotide binding site and inhibit the intrinsic nucleotide exchange. In an approach to overcome this limitation for mutated K-RasG12C, the thiol function of cysteine 12 was used to covalently trap inhibitors. A set of GDP-derived inhibitors was developed to directly target the nucleotide binding site.
Ostrem et al. Remarkably, Ras—GTP exists in at least two distinct conformational states, which interconvert with rate constants on the millisecond timescale. Impairment of Post-translational Modification of Ras Ras-dependent signaling requires the correct intracellular localization of Ras proteins predominantly at the plasma membrane, mediated by membrane-anchoring lipid residues at the C terminus.
Therefore, impairment of Ras localization has been explored to inhibit oncogenic Ras signaling. FarnesyltransfeRase inhibitors FTIs interrupt this biosynthetic sequence, leading to nonlipidated cytosolic Ras. Several FTIs reached late-stage clinical trials but ultimately failed, mostly because of alternative geranylgeranylation of the K-Ras and N-Ras isoforms.
However, a number of studies report promising preclinical and clinical results for FTIs as single agents or in combination with other conventional anticancer agents. Conclusion Ras signaling pathways constitute central drivers of cancer development and therefore strategies have been sought for development of potent Ras inhibitors effective in vivo as well.
Since Ras signaling pathway is a complex network controlled by several feedback loops, blocking a single pathway may not be adequate to achieve a reduction of Ras signaling to a therapeutically significant level.
Therefore, combined therapies targeting Ras and other oncoproteins in parallel may be required to control tumors. No funding was received in the publication of this article. E: atanubioinfo gmail.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author s and source are given appropriate credit.
Somatic DNA mutational analysis has transformed how we characterize existing cancer and select treatments. For example, circulating tumour cell-free DNA cfDNA can be used to select targeted therapies, monitor treatment response and detect disease recurrence. Molecular diagnosis and screening of cancer can be approached either in a broad, high-volume manner, or through using targeted, informed searches for specific genes.
Technique selection will be critical in balancing patient benefit against healthcare resource cost, and physicians will need to consider how to prioritise their investigations in order to support accurate and efficacious […].
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